The present invention relates to a treatment of central nervous system disorders, cognitive deficits and dementias associated with a diversity of conditions, including age-related or glucocorticoid-related declines in cognitive function such as those seen in Alzheimer's and associated dementias, major depressive disorder, psychotic depression, anxiety, panic disorder, post traumatic stress disorder, depression in Cushing's syndrome, and treatment resistant depression, using 11β-HSD1 inhibitors.
11-β-hydroxysteroid dehydrogenase Type 1 enzyme (11β-HSD-1) is a low affinity enzyme with Km for cortisone in the micromolar range that prefers NADPH/NADP+ (nicotinamide adenine dinucleotide phosphate) as cofactors. 11β-HSD-1 is widely expressed and particularly high expression levels are found in liver, brain, lung, adipose tissue, and vascular smooth muscle cells. In vitro studies indicate that 11β-HSD-1 is capable of acting both as a reductase and a dehydrogenase. However, many studies have shown that it functions primarily as a reductase in vivo and in intact cells. It converts inactive 11-ketoglucocorticoids (i.e., cortisone or dehydrocorticosterone) to active 11-hydroxyglucocorticoids (i.e., cortisol or corticosterone), and thereby amplifies glucocorticoid action in a tissue-specific manner.
11β-HSD-1 is expressed in mammalian brain, and published data indicates that elevated levels of glucocorticoids may cause neuronal degeneration and dysfunction, particularly in the aged (de Quervain et al.; Hum Mol Genet. Vol. 13 pages 47-52, 2004; Belanoff et al. J. Psychiatr Res. Vol. 35, pages 127-35, 2001). Evidence in rodents and humans suggests that prolonged elevation of plasma glucocorticoid levels impairs cognitive function that becomes more profound with aging. (See, A. M. Issa et al., J. Neurosci. Vol. 10, pages 3247-3254, 1990; S. J. Lupien et. al., Nat. Neurosci., Vol. 1, pages 69-73, 1998; J. L. Yau et al. Neuroscience, Vol. 66, pages 571-581, 1995). Chronic excessive cortisol levels in the brain may result in neuronal loss and neuronal dysfunction. (See, D. S. Kerr et al., Psychobiology, Vol. 22 pages 123-133, 1994, C. Woolley, Brain Res. Vol. 531 pages 225-231, 1990, P. W. Landfield, Science, Vol. 272 pages 1249-1251, 1996). Furthermore, glucocorticoid-induced acute psychosis exemplifies a more pharmacological induction of this response, and is of major concern to physicians when treating patients with these steroidal agents (Wolkowitz et al.; Ann NY Acad Sci. Vol. 1032 pages 191-194, 2004). It has been recently shown that 11β-HSD-1 mRNA is expressed in human hippocampus, frontal cortex and cerebellum, and that treatment of elderly diabetic individuals with the non-selective 11β-HSD-1 and 11β-HSD-2 inhibitor carbenoxolone improved verbal fluency and memory (Thekkapat et al., Proc Natl Acad Sci USA. Vol. 101, pages 6743-6749, 2004). Excessive glucocorticoid levels also affects psychopathology, as shown in animal models, it leads to increased anxiety and aggression. Chronic elevation of cortisol has been also associated with depression in Cushing's disease (McEwen, Metab. Clin. & Exp. Vol. 54, pages 20-23 (2005)). A number of animal and clinical studies have provided evidence for the correlation between increases in glucocorticoid levels and neuropsychiatric disorders such as major depressive disorder, psychotic depression, anxiety, panic disorder, post traumatic stress disorder, and depression in Cushing's syndrome (Budziszcwska, Polish J. of Pharmacol. Vol. 54 pages 343-349, 2002; Ströhle and Holboer, Pharmacopsychiatry Vol. 36 pages S207-S214, 2003; DeBattista and Belanoff, TRENDS in Endocr. Metab., Vol. 17 pages 117-120, 2006; Norman and Burrows, Expert Rev. Neurotherapeutics Vol. 7, pages 203-213, 2007).
The compounds disclosed in the present application are selective inhibitors of 11β-HSD-1 as described in U.S. patent application publication Nos. 2005/0277747, 2006/0281773, and 2006/0149070, and in U.S. patent application Ser. No. 11/697,044, which are hereby incorporated herein by reference. These compounds are useful in the treatment of non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome, and other diseases and conditions that are mediated by excessive glucocorticoid action.
The present application describes the utility of these selective inhibitors of 11β-HSD-1 in the treatment of central nervous system disorders, age-related or glucocorticoid-related declines in cognitive function such as those seen in Alzheimer's and associated dementias, major depressive disorder, psychotic depression, anxiety, panic disorder, post traumatic stress disorder, depression in Cushing's syndrome, and treatment resistant depression.